Substituted phenoxyacetic acid diethylamides as anesthetics



United States Patent US. Cl. 424311 0 Claims ABSTRACT OF THE DISCLOSUREThe compounds are of the class of substituted phenoxyacetic aciddiethylamides which are useful as short-acting, quickly metabolizedanesthetic agents. An illustrative embodiment is 2 methoxy 4(3'-acetoxy-propyl)phenoxy acetic acid diethylamide.

DETAILED DISCLOSURE This application is a continuation of Ser. No.431,214, filed Feb. 8, 1965, now abandoned.

The present invention concerns new aryloxyacetic acid amides, as well asprocesses for the production of these compounds which are valuablepharmaceuticals and intermediate products for the production thereof.

More in particular, this invention concerns, in a first aspect thereof,novel short-acting, quickly metabolized anesthetic agents which areespecially well suited for administration in the form of solutions forintravenous injection, in a very short time, with good veincompatibility.

Short-acting, quickly metabolized, intravenously ap plied anestheticsshould possess certain properties in order to be practically useful.Among these properties must be a suflicently high activity to permitachievement of a narcosis of stage IV with a dose of less than 50mg./kg. of body weight applied to test animals such as rabbits. Thismeans that the active ingredient can be administered to a patient in theform of injection solutions containing not more than 5% by weight of theactive substance, and that the amount of such solution that must beadministered to obtain the desired anesthetic effect does not exceed avolume of 20 millilitres. Active substances which must be administeredin larger volumes and/or in higher concentrations are not permissiblebecause they lead to venous irritation and cannot be administered in theshort time, e.g. a fraction of a minute, which is necessary to achieve aquick, sufficiently deep narco-sis.

Esters of acetic acid and N,N-disubstituted 2-methoxy-4-hydroxymethyl-phenoxyacetic acid amides are not of sufiicient activityto permit preparation of injection solutions fulfilling the abovemedical requirements, and certain homologous esters of acetic acid andN,N-disubsti tuted 2 methoxy-4-(2-hydroxy-ethyl)-phenoxyacetic acidamides cause convulsions and other undesirable side effects and possesssuch high toxicity that they can not be used as anesthetics.

We have now found that, unexpectedly, a narrow group of esters of aceticacid with certain N,N-disubstituted 2- alkoxy-4- 3 '-hydroxy-propyl)-phenoxyacetic acid amides and 2alkoxy-4-(3'-hydroxy-l-propenyl)-phenoxyacetic acid amides are verysatisfactory short acting anesthetics which lend themselves to thepreparation of injection solutions fulfilling the above-describedmedical requirements.

Patented Dec. 16, 1969 ICC The anesthetic agents according to theinvention are, or contain as the anestically active ingredient, acompound of the formula wherein R represents one of the radicals3-acetoxy-propyl and 3-acetoxy-1-propenyl which correspond to theformulae CH -COOCH CH CH and and R represents methyl or ethyl, and canbe used as short-acting anesthetics particularly for the treatment ofsimple and short but painful surgical operations on ambulant patients.They are administered preferably parenterally, in particularintravenously, as a dispersion or as solution in a mixture of water anda clinically acceptable solubility promoter.

These compounds are produced by acetylation of a hydroxyl compound ofthe formula C 211 (II) wherein X is the ethylene or vinylene radical,and R has the same meaning as in Formula I. One way to obtain a compoundof Formula I consists in esterifying a hydroxyl compound of Formula IIwith acetic acid. The reaction is performed, for example, in thepresence of a catalyst such as, e.g. concentrated sulphuric acid, dryhydrogen chloride, phosphoric acid or p-toluene sulphonic acid, inexcess acetic acid, or it is performed in the presence of a carbodiimidesuch as, e.g. dicyclohexylor di-p-tolylcarbodiimide, and also in thepresence of N,N- carbonyl-di-imidazole in a solvent such as dry dioxan,tetrahydrofuran or dimethyl formamide. If, instead of the free aceticacid, a reactive functional derivative thereof such as a halide oracetanhydride is reacted with a hydroxyl compound of Formula II, thenthe reaction is preferably performed in the presence of an acid bindingagent. Suitable acid binding agents are, e.g. pyridine andtriethylamine-they can be used in an excess as solvents or potassiumcarbonate in a solvent or diluent such as benzene, toluene or acetone.

Another variation of the process for the acetylation of hydroxylcompounds of general Formula II consists in reacting them with ketene orwith a compound which liberates it, such as acetic acid isopropenylester, the reaction preferably being performed in the presence of acatalyst such as concentrated sulphuric acid, p-toluene sulphonic acidor sodium acetate, in a solvent or diluent such as acetone or dioxan.

If desired, a compound of general Formula I, wherein R is represented bythe S-acetoxy-l-propenyl radical, is reduced to the correspondingcompound with the 3-acetoxy-propyl radical R. The reduction isperformed, for example, by means of hydrogen in the presence of acatalyst such as Raney nickel, e.g. in a lower alkanol or dioxan, at atemperature of about 20-l00 and under a pressure of about latmospheres.

The starting compounds of general Formula II are also new compounds.

To produce a compound of Formula II, a substituted phenol of the formulaOz s (III) wherein X and R have the meanings given above, is reacted inthe presence of an'acid binding agent, with a reactive ester ofN,N-diethyl glycolamide such as N,N- diethyl chloroacetamide,N,N-diethyl bromacetamide or N,N-diethyl-Z-p-tolylsulphonyloxyacetamide,or a salt of a phenol of Formula III, particularly an alkali metal salt,is reacted with one of the above named reactive esters of N,N-diethylglycolamide. Suitable acid binding agents are, preferably, sodiumhydroxide or a sodium alcoholate and, as solvent, a lower alkanol or amixture of alkanol and Water is suitable. Other suitable acid bindingagents are sodium and potassium carbonate in acetone or another organicsolvent. Also the sodium salts of the phenols of Formula III can be usedas starting materials and, in this case, a solvent not containinghydroxyl groups such as benzene, toluene, xylene, or particularly,dimethyl formamide, is used.

Of the compounds of Formula II, 3-(3'-methoxy 4"-hydroxy-phenyl)-2-propen-1-ol (coniferyl alcohol) and 3-(3-methoxy-4-hydroxy-phenyl) 1 propanol (dihydroconiferyl alcohol) areknown. The 3-ethoxy-analogues are obtained analogously to proceduresused for the preparation of the known 3-methoxy-compounds.

As mentioned above, the new anesthetic agents falling under Formula Iare administered, preferably, intravenously. The liquids for injetcioncontain 1-5% of active substance, water, a solubilizing agent oremulsifying agent. The following compounds can be used as solubilizingor emulsifying agents: propylene glycol, sodium benzoate or the sodiumsalt of a hydroxybenzoic acid (analogously to the German Patent No.1,091,288), water soluble salts of bile acids such as sodiumdehydrocholate, morpholine desoxycholate, ethanolamine cholate,(analogously to German Patent No. 1,089,510), salts of a-naphthyl aceticacid with sodium or organic bases such as morpholine and diethanolamine(analogously to German Patent No. 1,147,055), as well as histamine andpyrogen free inositol phosphatide preparations and lecithin preparationhaving a low content of oil, optionally with partical glycerides ofhigher fatty acids such as monoor di-olein, and/or their polyoxyethylenederivatives (analogously to US. Patent No. 3,044,931).

A dispersion of 1-5% of active substance, 10-25%, generally 15-20% ofpolyoxyethylene derivative of ricinoleic acid or of its glycerides, e.g.the commercial product Cremophor EL, 5-15%, generally about of propyleneglycol, 15%, generally about 2.5%, of poly-(N vinyl-2-pyrrolidone), egthe commercial product Kollidon 25 of medium molecular weight of about20,000 to 25,000, and optionally, up to about 1.5% of glucose, isparticularly suitable.

Such a dispersion can be produced, for example, as follows:

(a) 2.5 g. of 2-methoxy-4-(3'-acetoxy-propyl)-phenoXyacetic aciddiethylamide are dissolved, with slight heating, in a mixture of 15.0 g.of Cremophor EL, (den sity 1050-1070 at 25 C., viscosity 550-850 cp. at25 C., saponification number 56-66, hydroxyl number 57-80, manufacturedby BASF, Ludwigshafen, Germany), and 10.0 g. of propylene glycol. 2.5 g.of Kollidon 25 (biologically tested poly-(N-vinyl-2-pyrrolidone)) and1.5 g. of glucose are dissolved in 60 g. of distilled water. The twosolutions are mixed and the volume is made up to 100 ml. with distilledwater. After filtering through a glass filter G4, the solution is filledinto colourless ampoules of 5 or 10 ml. and sterilised in an autoclavefor 20 minutes at 120 and 1 atm. excess pressure. The solutions soproduced contain 25 mg. of active substance per millilitre.

(b) A solution having the same content of active substance is obtainedon using 15.0 g. of propylene glycol, 5.0 g. of Kollidon 25; no glucoseand the same amounts of the other components.

The following non-limitative examples illustrate the production of thenew compo f g l Formula I,

ml. means millilitre, and torr means mm. Hg.

EXAMPLE 1 (a) A solution of 22.8 g. of3-(3-methoxy-4-hydroxyphenyl)-1-propanol (dihydroconiferyl alcohol) inml. of anhydrous ethanol is added to a solution of 2.9 g. of sodium in100 ml. of anhydrous ethanol and the mixture is refluxed for 15 minutes.0.5 g. of sodium iodide and 20.6 g. of chloroacetic acid diethylamideare added, the latter dropwise, and the whole is refluxed until thereaction of the mixture is neutral. After cooling to 20, precipitatedsodium chloride is filtered off and washed with ethanol and the filtrateis evaporated in vacuo. The residue is taken up in chloroform, washedwith 2 N sodium hydroxide solution and water, dried over sodium sulfateand concentrated. Distillation of the residue under 0.009 torr yieldsZ-methoxy 4 (3'-hydroxypropyl)-phenoxyacetic acid diethylamide whichboils at 218-223" under this pressure.

(b) A solution of 15 g. of 2-methoxy-4-(3-hydroxypropyl)-phenoxyaceticacid diethylamide in 15 ml. of pyridine and 15 ml. of acetic acidanhydride is left standing for 48 hours at 20 after which it isevaporated at 60 under 12 torr. 24 ml. of saturated, aqueous sodiumcarbonate solution are added to the residue, the mixture is extractedwith diethyl ether, the ethereal solution is washed with saturatedsodium chloride solution, dried over sodium sulfate and evaporated invacuo. Distillation of the residue at 0.002 torr yields2-methoxy-4-(3'-acetoxypropyl)-phenoxyacetic acid diethylamide, whichboils at 180-187 under this pressure. n 1.5155.

(c) From 22.6 g. of 3-(3-methoxy-4-hydroxyphenyl)- 2-propen-1-ol(coniferyl alcohol) 2-methoxy-4-(3-hydroxy-1-propenyl)-phenoxyaceticacid diethylamide, B.P. 213/ 0.005 torr is obtained analogously to (a),and therefrom 2-methoxy 4 (3-acetoxy-1'-propenyl)-phenoxyacetic aciddiethylamide, B.P. 176177/0.002 torr, n 1.5448, is produced analogouslyto (b).

EXAMPLE 2 (a) 166.2 g. of 3-hydroxy 4 ethoxy-benzaldehyde (bourbonal)and 230 g. of malonic acid are dissolved as well as possible by heatinggently in 500 ml. of pyridine, 12 ml. of piperidine are added to themixture and the whole is gently stirred for 3 hours at room temperature.It is then heated for about 2 hours on a steam bath until thedevelopment of carbon dioxide decreases. The reaction mixture is thenpoured into a mixture of 1 kg. of ice and 600 ml. of concentratedsulfuric acid whereupon the reaction product gradually crystallizes.After standing for 1 hour at 0, the reaction product is filtered offunder suction and washed three times with ml. of cold water each time.The filter cake is dissolved in 250 ml. of acetone and ml. of water, thesolution is filtered, 400 ml. of water are added and the whole is keptfor 15 hours at 0. The 3-hydroxy-4-ethoxy-cinnamic acid whichcrystallizes out is filtered off under suction, washed with cold waterand dried for 5 hours at 80 under 11 torr, M.P. 156-157".

(b) 104 g. of 3-ethoxy-4-hydroxycinnamic acid are dissolved, whilegently heating, in 520 ml. of anhydrous ethanol, the solution issaturated with dry gaseous hydrogen chloride, then refluxed for 5 hoursand then evaporated in vacuo. The residue is taken up in diethyl ether,the ethereal solution is washed with saturated sodium hydrogen carbonatesolution and with water, dried over sodium sulfate and evaporated invacuo. Distillation of the residue under 0.01 torr, yields3-ethoxy-4-hydroxycinnamic acid ethyl ester which boils at -185 underthis pressure. It solidifies into crystals which melt at 54-56.

(c) 44.8 g. of 3-ethoxy-4-hydroxycinnamic acid ethyl ester are dissolvedin 500 ml. of anhydrous ethanol and the solution is hydrogenated at 20under atmospheric pressure with hydrogen in the presence of palladiumcharcoal until no more hydrogen is taken up. The catalyst is filteredoff under suction and washed with ethanol. The filtrate is evaporated invacuo. The residue is recrystallized from diethylether/pentane whereupon3-ethoxy-4- hydroxy-hydrocinnamic acid ethyl ester is obtained whichmelts at 3839.5.

(d) A solution of 29.2 g. of 3-ethoxy-4-hydroxy-hydrocinnamic acid ethylester in 50 ml. of anhydrous diethyl ether is added dropwise whilevibrating well to a suspension of 9.3 g. of lithium aluminium hydride in150 ml. of anhydrous diethyl ether, the addition being so made that thereaction mixture lightly boils. On completion of the dropwise addition,the reaction mixture is refluxed for another 3 hours while cooling withice and vibrating well. 100 ml. of diethyl ether are then added afterwhich carbon dioxide is introduced until saturation is reached. Theethereal phase is separated, the aqueous phase is extracted with ethylacetate, the combined organic phases are washed with saturated sodiumchloride solution, dried over sodium sulfate and evaporated in vacuo.The residue is recrystallized from diethyl ether/pentane; the 3-(3-ethoxy-4-hydroxyphenyl)-propane-1-ol obtained melts at 63-64".

(e) 2-ethoxy-4-(3-hydroxypropyl)-pnenoxyacetic acid diethylamide, B.P.215 0.06 torr, is produced from the phenyl propanol derivative obtainedaccording to (d) analogously to (1a) with chloroacetic aciddiethylamide.

(f) 2-ethoXy-4-(3 acetoxypropyl)-phenoxyacetic acid diethylamide, B.P.200207/0.02 torr, n 1.5114, is

obtained analogously to (1b) from the 2-ethoxy-4-(3- hydroxypropyl)-phenoxyacetic acid diethylamide prepared according to (d).

EXAMPLE 3 (a) 29.0 g. of 3-eth0xy-4-hydroxycinnamic acid ethyl ester,obtained according to Example 1b, are reduced analogously to Example 2d,to 3-(3-ethoxy-4'-hydroxyphenyl) -2-propen- 1 -ol (b) 2 ethoxy 43-hydroxy-1'-propenyl)-phenoxyacetic acid diethylamide is produced fromthe reaction product of (a) analogously to Example la with chloroaceticacid diethylamide.

(c) From the reaction product of (b), 2-ethoxy-4-(3'-acetoxy-l'-propenyl)-phenoxyacetic acid diethylamide is obtained byacetylation analogously to Example lb.

What is claimed is:

1. A therapeutical composition in dosage unit form comprising (1) anamount of 1 to 5% of a compound of the formula wherein:

R is 3-acetoxy-propyl or 3-acetoxy-l-propenyl, and (2) an effectiveamount of pharmaceutically acceptable solubilizing agent, and

(3) a liquid pharmaceutically acceptable carrier;

wherein said solubilizing agent and said liquid carrier comprise (a)10-25% of polyoxyethylene derivative of ricinoleic acid or of itsglycerides, (b) 5l5% of propylene glycol, (c) 15% ofpoly-(N-vinyl-2-pyrrolidone) of medium molecular Weight, (d) 01.5% ofglucose, and (e) distilled water.

2. A therapeutical composition as defined in claim 1 wherein saidcompound is 2-methoxy-4-(3'-acetoxy-propyl)-phenoXy-acetic acid,diethylamide.

3. A therapeutical composition as defined in claim 1 wherein saidcompound is 2-eth0xy-4-(3-acetoxy-propyl)-phenoxy-acetic aciddiethylamide.

4. A therapeutical composition as defined in claim 1 wherein saidcompound is 2-methoxy-4-(3-acetoxy-l'- propenyl)-phenoxyacetic aciddiethylamide.

5. A therapeutical composition as defined in claim 1 wherein saidcompound is 2-ethoxy-4-(3'-acetoxy-1- propenyl)-phenoxyacetic aciddiethylamide.

6. A process for producing an anesthetic ellect in a mammal whichcomprises intravenously administering to said mammal an effective amountof a compound of the formula wherein:

R is 3-acetoxy-propyl or 3-acetoxy-l-propenyl, and R is methyl or ethyl.

7. A process as claimed in claim 6 wherein said compound is2-methoxy-4-(3'-acetoxy-propyl)-phenoxy-acetic acid diethylamide.

8. A process as claimed in claim 6 wherein said compound is 2-ethoxy-4-3 -acetoxy-propyl) -phenoxy-acetic acid diethylamide.

9. A process as claimed in claim 6 wherein said compound is2-methoxy-4-(3-acetoxy-l'-propenyl)-phenoxy acetic acid diethylamide.

10. A process as claimed in claim 6 wherein said compound is 2-ethoxy-4-3 -acetoxy-1-propyl -phenoxy-acetic acid diethylamide.

References Cited UNITED STATES PATENTS 3,012,936 12/1961 Stoll.

ALBERT T. MEYERS, Primary Examiner JEROME D. GOLDBERG, AssistantExaminer

